Human antibodies to the glucagon receptor and methods of use thereof for lowering blood glucose or ketone levels

Abstract

The present invention provides antibodies that bind to the human glucagon receptor, designated GCGR and methods of using same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to human GCGR. The antibodies of the invention are useful for lowering blood glucose levels and blood ketone levels and are also useful for the treatment of diseases and disorders associated with one or more GCGR biological activities, including the treatment of diabetes, diabetic ketoacidosis and long-term complications associated with diabetes, or other metabolic disorders characterized in part by elevated blood glucose levels.

What is claimed is: 
     
       1. An isolated human antibody or antigen-binding fragment thereof that specifically binds human glucagon receptor (hGCGR), comprising a heavy chain variable region (HCVR) having an amino acid sequence that has at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 86; and a light chain variable region (LCVR) having an amino acid sequence that has at least 95% sequence identity to the amino acid sequence set forth in SEQ ID NO: 88;
 wherein any sequence variability is present only within the one or more framework regions of the HCVR and/or within the one or more framework regions of the LCVR. 
 
     
     
       2. The isolated antibody or antigen-binding fragment thereof of  claim 1 , comprising an HCVR having an amino acid sequence that has at least 98% sequence identity to the amino acid sequence set forth in SEQ ID NO: 86. 
     
     
       3. The isolated antibody or antigen-binding fragment thereof of  claim 1 , comprising an LCVR having an amino acid sequence that has at least 98% sequence identity to the amino acid sequence set forth in SEQ ID NO: 88. 
     
     
       4. The isolated antibody or antigen-binding fragment of  claim 1 , comprising an HCVR/LCVR sequence pair that has at least 95% sequence identity to each of SEQ ID NOs: 86/88. 
     
     
       5. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
       6. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof of  claim 1 , and a second therapeutic agent comprising an isolated antibody, or an antigen-binding fragment thereof, that specifically binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), and a pharmaceutically acceptable carrier or diluent. 
     
     
       7. A method for lowering blood glucose or ketone levels, or for treating a condition or disease associated with, or characterized in part by high blood glucose or ketone levels, or at least one symptom or complication associated with the condition or disease, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of  claim 5 , to a patient in need thereof, such that blood glucose or ketone levels are lowered or that the condition or disease is mediated, or at least one symptom or complication associated with the condition or disease is alleviated or reduced in severity. 
     
     
       8. The method of  claim 7 , wherein the condition or disease is selected from the group consisting of diabetes, impaired glucose tolerance, obesity, nephropathy, neuropathy, retinopathy, cataracts, stroke, atherosclerosis, impaired wound healing, diabetic ketoacidosis, hyperglycemia, hyperglycemic hyperosmolar syndrome, perioperative hyperglycemia, hyperglycemia in the intensive care unit patient, hyperinsulinemia, the metabolic syndrome, insulin resistance syndrome and impaired fasting glucose. 
     
     
       9. The method of  claim 7 , wherein the pharmaceutical composition is administered to the patient in combination with a second therapeutic agent. 
     
     
       10. The method of  claim 9 , wherein the second therapeutic agent is selected from the group consisting of insulin, a biguanide, metformin, a sulfonylurea, glyburide, glipizide, a peroxisome proliferator-activated receptor (PPAR) gamma agonist, pioglitazone, rosiglitazone, an alpha glucosidase inhibitor, acarbose, voglibose, glucagon-like peptide 1, pramlintide, a glucagon antagonist, and a second GCGR antagonist. 
     
     
       11. The method of  claim 9 , wherein the second therapeutic agent is a nucleic acid that inhibits the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) and is selected from an anti-sense molecule, a double stranded RNA, and an siRNA. 
     
     
       12. The method of  claim 9 , wherein the second therapeutic agent is a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) inhibitor. 
     
     
       13. The method of  claim 12 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. 
     
     
       14. The method of  claim 9 , wherein the second therapeutic agent is an isolated antibody, or an antigen-binding fragment thereof, that specifically binds to human proprotein convertase subtilisin/kexin type 9 (PCSK9). 
     
     
       15. The method of  claim 9 , wherein the second therapeutic agent is an inhibitor of angiopoietin-like protein 3, an inhibitor of angiopoietin-like protein 4, an inhibitor of angiopoietin-like protein 5, or an inhibitor of angiopoietin-like protein 6. 
     
     
       16. An isolated human antibody or antigen-binding fragment thereof that specifically binds human glucagon receptor (hGCGR), comprising an HCVR and an LCVR, wherein the HCVR has an amino acid sequence of SEQ ID NO: 86. 
     
     
       17. The isolated antibody or antigen-binding fragment of  claim 16 , wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 68, 78, 98, 108, 118, 128, 138, and 148. 
     
     
       18. An isolated human antibody or antigen-binding fragment thereof that specifically binds human glucagon receptor (hGCGR), comprising an HCVR and an LCVR, wherein the LCVR has an amino acid sequence of SEQ ID NO: 88. 
     
     
       19. The isolated antibody or antigen-binding fragment of  claim 18 , wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 70, 90, 106, 110, 126, 130 and 146. 
     
     
       20. An antibody or antigen-binding fragment thereof that competes for specific binding to hGCGR with an antibody or antigen-binding fragment comprising the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence set forth in SEQ ID NO: 86; and the CDRs of a light chain variable region (LCVR) having an amino acid sequence set forth in SEQ ID NO: 88. 
     
     
       21. An antibody or antigen-binding fragment thereof that binds the same epitope on hGCGR as an antibody or antigen-binding fragment comprising the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having an amino acid sequence of SEQ ID NO: 86; and the CDRs of a light chain variable region (LCVR) having an amino acid sequence of SEQ ID NO: 88.